University of North Carolina Lineberger Comprehensive Cancer Center researchers identified the culprit that keeps cancer-killing immune cells from reaching pancreatic cancer tumors.
In a study in Cancer Immunology Research, scientists led by UNC Lineberger’s Yuliya Pylayeva-Gupta, PhD, implicated B-cells, a type of immune cell, in the releasing of signals to keep T-cells from reaching pancreatic tumors to kill tumor cells.
From preclinical studies of pancreatic ductal adenocarcinoma in mice, researchers identified B-cells as the source of interleukin-35, or IL-35. Pylayeva-Gupta’s lab found in previous studies that IL-35 is a broadly immunosuppressive signal for T-cells in pancreatic cancer models.
“We find that IL-35 produced by B-cells acts directly on cytotoxic T-cells and prevents their activation and migration to target the tumor cells,” Pylayeva-Gupta said.
The study also reveals details on how IL-35 could be helping to suppress T-cell activity against tumors by initiating the action of STAT3, which is a transcription factor. Specifically, STAT3, once activated by IL-35, contributes to the T-cells’ decreased migration and activation.
The researchers reported that both STAT3 and IL-35 could be therapeutic targets in pancreatic cancer. When they blocked STAT3 in T-cells, they saw that it helped control tumor growth.
Researchers said these findings have potential implications for pancreatic cancer responses to anti-PD1 immunotherapy, since the efficacy of immunotherapy can be dependent on ability of T-cells to reach the tumor site.
While researchers don’t understand what exactly causes the B-cells to release signals that help protect tumors from a T-cell attack, they believe it could be the tumor itself that triggers the B-cells initially.
B-cells help the body defend itself by producing antibodies that fight disease. Pylayeva-Gupta said that in addition to their defense mechanisms, B-cells can help suppress immune responses to ameliorate auto-immune disorders. It could be that tumors can use this mechanism to their advantage.
“There must be some sort of cancer-driven mechanisms that stimulate the production of IL-35 by B-cells,” she said. “We’re trying to find out what those mechanisms are and whether we can take additional approaches to target them in cancer.”
The researchers also identified markers for human IL-35-producing B-cells and generated specific genetic signature indicating the presence of the immunosuppressive B-cells in samples from human pancreatic cancer tumors as well as other tumor types.
Authors and Disclosures
In addition to Pylayeva-Gupta, other authors included Bhalchandra Mirlekar, Daniel Michaud, Samuel J. Lee, Nancy Kren, Cameron Harris, Kevin Greene, Emily C. Goldman, Gaorav P. Gupta, Ryan C. Fields, William G. Hawkins, David G. DeNardo, Naim Rashid, Jen Jen Yeh, Autumn McCree, Benjamin G. Vincent and Dario A.A. Vignali.
Conflicts of interest: Vignali has submitted patents pending or granted covering IL-35. He is entitled to a share in net income generated from the licensing of these patent rights for commercial development. He also consults for several biopharmaceutical companies.
The study was supported by the National Cancer Institute, the University Cancer Research Fund, an AACR-PanCAN Pathway to Leadership Grant, the V Foundation for Cancer Research, Concern Foundation Conquer Cancer Now Award, a WUSTL SPORE Career Enhancement Award grant from the NCI, a Cancer Cell Biology Training Program grant and the National Institutes of Health.